Combination of a CB1 receptor antagonist and of sibutramine, the pharmaceutical compositions comprising them and their use in the treatment of obesity

ABSTRACT

The present invention relates to the combination of a CB1 receptor antagonist and of sibutramine, to the pharmaceutical compositions comprising them and to their use in the treatment of obesity.

The present invention relates to the combination of a CB1 receptorantagonist and of sibutramine, to the pharmaceutical compositionscomprising them and to their use in the treatment of obesity.

CB1 receptor antagonists are known for their effect on food intake andtheir use as anorexigenic (G. Colombo et al., Life Sciences, 63 (8),113-117 (1998); J. Siamand et al., Behavioural Pharmacol., 9, 179-181(1998)).

Sibutramine (BTS 54524;N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine;Meridia^(R), Reductil^(R)), its hydrate and its pharmaceuticallyacceptable salts and in particular its hydrochloride reduces food intakeand is of use in the treatment of obesity (WO 90/061110; D. H. Ryan etal., Obesity Research, 3 (4), 553 (1995); H. C. Jackson et al., BritishJournal of Pharmacology, 121, 1758 (1997); G. Fanghanel et al., Inter.J. Obes., 24 (2), 144 (2000); G. A. Bray et al., Obes. Res., 7 (2), 189(1999)).

It has now been found that the combination of sibutramine, its hydrateand its pharmaceutically acceptable salts and of a CB1 receptorantagonist exhibits a synergistic effect in reducing food consumptionand is thus of use in the treatment of obesity.

The combination can also comprise several CB1 receptor antagonists.

Use may in particular be made, among CB1 receptor antagonists, of theazetidine derivatives disclosed in WO 00/15609, WO 01/64633 and WO01/64634 of formula:

in which

-   either R represents a chain (A) or (B) and-   R₁ represents a methyl or ethyl radical,-   R₂ represents either an aromatic chosen from phenyl, naphthyl or    indenyl, these aromatics being unsubstituted or substituted by one    or more halogen, alkyl, alkoxy, —CO-alk, hydroxyl, —COOR₅, formyl,    trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,    —NR₆R₇, —CO—NH—NR₆R₇, —N(alk)COOR₈, cyano, —CONHR₉, —CO—NR₁₆R₁₇,    alkylsulfanyl, hydroxyalkyl, —O-alk-NR₁₂R₁₃ or alkylthioalkyl, or a    heteroaromatic chosen from the benzofuryl, benzothiazolyl,    benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,    2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl,    isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,    1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl rings, it being    possible for these heteroaromatics to be unsubstituted or    substituted by a halogen, alkyl, alkoxy, —COOR₅, trifluoromethyl,    trifluoromethylsulfanyl, trifluoromethoxy, nitro, —NR₆R₇,    —CO—NH—NR₆R₇, cyano, —CONHR₉, alkylsulfanyl, hydroxyalkyl or    alkylthioalkyl,-   R₃ and R₄, which are identical or different, represent either an    aromatic chosen from phenyl, naphthyl or indenyl, these aromatics    being unsubstituted or substituted by one or more halogen, alkyl,    alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy,    —CO-alk, cyano, —COOR₅, —CONR₁₀R₁₁, —CO—NH—NR₆R₇, alkylsulfanyl,    hydroxyalkyl, -alk-NR₆R₇ or alkylthioalkyl, or a heteroaromatic    chosen from the benzofuryl, benzothiazolyl, benzothienyl,    benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,    2,3-dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl,    quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl rings,    it being possible for these heteroaromatics to be unsubstituted or    substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl,    trifluoromethoxy, cyano, —COOR₅, —CO—NH—NR₆R₇, —CONR₁₀R₁₁,    -alk-NR₆R₇, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,-   R₅ is an alkyl radical or a phenyl radical optionally substituted by    one or more halogen atoms,-   R₆ and R₇, which are identical or different, represent a hydrogen    atom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk    or hydroxyalkyl radical or else R₆ and R₇ form, together with the    nitrogen atom to which they are attached, a saturated or unsaturated    and mono- or bicyclic heterocycle having 3 to 10 ring members    optionally comprising another heteroatom chosen from oxygen, sulfur    and nitrogen and optionally being substituted by one or more alkyl,    —COalk, —COOalk, —CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo,    hydroxyalkyl, -alk-O-alk or —CO—NH₂ radicals,-   R₈ represents an alkyl radical,-   R₉ represents a hydrogen atom or a radical of the type alkyl or    alkyl substituted by dialkylamino, phenyl, cycloalkyl (optionally    substituted by —COOalk) or a saturated or unsaturated and mono- or    bicyclic heterocycle having 3 to 10 ring members optionally    comprising one or more heteroatoms chosen from oxygen, sulfur and    nitrogen and optionally being substituted by one or more alkyl    radicals,-   R₁₀ and R₁₁, which are identical or different, represent a hydrogen    atom or an alkyl radical or else R₁₀ and R₁₁, form, together with    the nitrogen atom to which they are attached, a saturated mono- or    bicyclic heterocycle having 3 to 10 ring members optionally    comprising another heteroatom chosen from oxygen, sulfur and    nitrogen and optionally being substituted by an alkyl radical,-   R₁₂ and R₁₃, which are identical or different, represent a hydrogen    atom or an alkyl or cycloalkyl radical or else R₁₂ and R₁₃ form,    together with the nitrogen atom to which they are attached, a    saturated mono- or bicyclic heterocycle having 3 to 10 ring members    optionally comprising another heteroatom chosen from oxygen, sulfur    and nitrogen and optionally being substituted by an alkyl, —COalk,    —COOalk, —CO—NHalk, —CS—NHalk or —CO-alk-NR₁₄R₁₅ radical or a    saturated mono- or bicyclic heterocycle having 3 to 10 ring members    and comprising a heteroatom chosen from oxygen, sulfur and nitrogen,-   R₁₄ and R₁₅, which are identical or different, represent a hydrogen    atom or an alkyl or —COOalk radical,-   R₁₆ and R₁₇ form, together with the nitrogen atom to which they are    attached, a saturated mono- or bicyclic heterocycle having 3 to 10    ring members optionally comprising another heteroatom chosen from    oxygen, sulfur and nitrogen,-   R′ represents a hydrogen atom or a —CO-alk radical,-   or R represents a CHR₁₈ radical and-   R₁₈ represents an —NHCOR₁₉ or —N(R₂₀)—Y—R₂₁ radical,-   Y is CO or SO₂,-   R₄ and R₃, which are identical or different, represent either an    aromatic chosen from phenyl, naphthyl and indenyl, these aromatics    being unsubstituted or substituted by one or more halogen, alkyl,    alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy,    —CO-alk, cyano, —COOH, —COOalk, —CONR₂₂R₂₃, —CO—NH—NR₂₄R₂₅,    alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl,    alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or    -alk-NH₂₂R₂₃, or a heteroaromatic chosen from the benzofuryl,    benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,    2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl,    imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl,    1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl rings, it being    possible for these heteroaromatics to be unsubstituted or    substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl,    trifluoromethoxy, cyano, —COOH, —COOalk, —CO—NH—NR₂₄R₂₅, —CONR₂₂R₂₃,    -alk-NR₂₄R₂₅, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,    alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or    hydroxyalkyl,-   R₁₉ represents an -alk-SO₂—R₂₆ radical, an -alk-SO₂—CH═CH—R₂₆    radical, a Het₁ radical substituted by —SO₂—R₂₆ or a phenyl radical    substituted by —SO₂—R₂₆ or -alk-SO₂—R₂₆,-   R₂₀ represents a hydrogen atom or an alkyl radical,-   R₂₁ represents a phenylalkyl, Het₁ or Ar₁ radical,-   R₂₂ and R₂₃, which are identical or different, represent a hydrogen    atom or an alkyl radical or else R₂₂ and R₂₃ form, together with the    nitrogen atom to which they are attached, a saturated mono- or    bicyclic heterocycle having 3 to 10 ring members optionally    comprising another heteroatom chosen from oxygen, sulfur and    nitrogen and optionally being substituted by one or more alkyl,-   R₂₄ and R₂₅, which are identical or different, represent a hydrogen    atom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk    or hydroxyalkyl radical or else R₂₄ and R₂₅ form, together with the    nitrogen atom to which they are attached, a saturated or unsaturated    mono- or bicyclic heterocycle having 3 to 10 ring members optionally    comprising another heteroatom chosen from oxygen, sulfur and    nitrogen and optionally being substituted by one or more alkyl,    —COalk, —COOalk, —CO—NHalk, —CS—NHalk, oxo, hydroxyalkyl, -alk-O-alk    or —CO—NH₂,-   R₂₆ represents an alkyl, Ar₁ or Het₁ radical,-   Ar₁ represents a phenyl, naphthyl or indenyl radical, these radicals    optionally being substituted by one or more halogen, alkyl, alkoxy,    cyano, —CO-alk, —COOH, —COOalk, —CONR₂₇R₂₈, —CO—NH—NR₂₉R₃₀,    alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR₂₉R₃₀, —NR₂₉R₃₀,    alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het,    —O-alk-NH-cycloalkyl, OCF₃, CF₃, —NH—CO-alk, —SO₂NH₂, —NH—COCH₃,    —NH—COOalk or Het or else on 2 adjacent carbon atoms by    dioxymethylene,-   Het₁ represents an unsaturated or saturated mono- or bicyclic    heterocycle having 3 to 10 ring members and comprising one or more    heteroatoms chosen from oxygen, sulfur and nitrogen which is    optionally substituted by one or more alkyl, alkoxy, vinyl, halogen,    alkoxycarbonyl, oxo, hydroxyl, OCF₃ or CF₃, the nitrogenous    heterocycles optionally being in their N-oxidized form,-   R₂₇ and R₂₈, which are identical or different, represent a hydrogen    atom or an alkyl radical or else R₂₇ and R₂₈ form, together with the    nitrogen atom to which they are attached, a saturated mono- or    bicyclic heterocycle having 3 to 10 ring members optionally    comprising another heteroatom chosen from oxygen, sulfur and    nitrogen and optionally being substituted by one or more alkyl    radicals,-   R₂₉ and R₃₀, which are identical or different, represent a hydrogen    atom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk    or hydroxyalkyl radical or else R₂₉ and R₃₀ form, together with the    nitrogen atom to which they are attached, a saturated or unsaturated    mono- or bicyclic heterocycle having 3 to 10 ring members optionally    comprising another heteroatom chosen from oxygen, sulfur and    nitrogen and optionally being substituted by one or more alkyl,    —COalk, —COOalk, —CO—NHalk, —CS—NHalk, oxo, hydroxyalkyl, -alk-O-alk    or —CO—NH₂ radicals,-   or R represents CHR₃₁ and-   R₃₁ represents an —N(R₃₂)R₃₃, —N(R₃₂)—CO—R₃₃ or —N(R₃₂)—SO₂R₃₄    radical,-   R₄ and R₃, which are identical or different, represent either an    aromatic chosen from phenyl, naphthyl and indenyl, these aromatics    being unsubstituted or substituted by one or more halogen, alkyl,    alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy,    —CO-alk, cyano, —COOH, COOalk, —CONR₂₂R₂₃, —CO—NH—NR₂₄R₂₅,    alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl,    alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR₇R₈,    or a heteroaromatic chosen from the benzofuryl, benzothiazolyl,    benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,    2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl,    isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl,    1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl rings, it being    possible for these heteroaromatics to be unsubstituted or    substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl,    trifluoromethoxy, cyano, —COOH, —COOalk, —CO—NH—NR₂₄R₂₅, —CONR₂₂R₂₃,    -alk-NR₂₄R₂₅, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,    alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or    hydroxyalkyl,-   R₃₂ represents a —C(R₃₅)(R₃₆)-Het₂, -Het₂, —C(R₃₅)(R₃₆)—Ar₂, Ar₂,    cycloalkyl or norbornyl radical,-   R₃₃ represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk,    -alk-CONR₂₂R₂₃, -alk-NR₂₂R₂₃, alkoxy, Ar₂, Het₂, —CH₂Ar₂, —CH₂Het₂    or alkyl radical, the latter optionally substituted by one or more    halogen,-   R₃₄ represents a hydroxyalkyl, -alk-COOalk, -alk-CONR₂₂R₂₃,    -alk-NR₂₂R₂₃, alkoxy, Ar₂, Het₂, —CH₂Ar₂, —CH₂Het₂ or alkyl radical,    the latter optionally substituted by one or more halogen,-   R₃₅ represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk,    -alk-CONR₂₂R₂₃, -alk-NR₂₂R₂₃, alkoxyalkyl, Ar₂, Het₂, —CH₂Ar₂,    —CH₂Het₂ or alkyl radical, the latter optionally substituted by one    or more halogen,-   R₃₆ represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk,    -alk-CONR₂₂R₂₃, -alk-NR₂₂R₂₃, alkoxyalkyl or alkyl radical, the    latter optionally substituted by one or more halogen,-   or else R₃₅ and R₃₆ form, together with the carbon atom to which    they are attached, a saturated mono- or bicyclic ring having 3 to 10    ring members optionally comprising another heteroatom chosen from    oxygen, sulfur and nitrogen and optionally being substituted by one    or more alkyl,-   Ar₂ represents a phenyl, naphthyl or indenyl radical, these various    radicals optionally being substituted by one or more halogen, alkyl,    alkoxy, —CO-alk, cyano, —COOH, —COOalk, —CONR₃₇R₃₈, —CO—NH—R₃₉R₄₀,    alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR₃₉R₄₀, —NR₃₉R₄₀,    alkylthioalkyl, formyl, CF₃, OCF₃, Het, —O-alk-NH-cycloalkyl,    SO₂NH₂, hydroxyl, hydroxyalkyl, —NHCOalk or NHCOOalk or on 2    adjacent carbon atoms by dioxymethylene,-   Het₂ represents an unsaturated or saturated mono- or bicyclic    heterocycle having 3 to 10 ring members and comprising one or more    heteroatoms chosen from oxygen, sulfur and nitrogen which is    optionally substituted by one or more alkyl, alkoxy, halogen,    alkoxycarbonyl, oxo or hydroxyl, the nitrogenous heterocycles    optionally being in their N-oxidized form,-   R₃₇ and R₃₈, which are identical or different, represent a hydrogen    atom or an alkyl radical or else R₃₇ and R₃₈ form, together with the    nitrogen atom to which they are attached, a saturated mono- or    bicyclic heterocycle having 3 to 10 ring members optionally    comprising another heteroatom chosen from oxygen, sulfur and    nitrogen and optionally being substituted by one or more alkyl,-   R₃₉ and R₄₀, which are identical or different, represent a hydrogen    atom or an alkyl radical or else R₃₉ and R₄₀ form, together with the    nitrogen atom to which they are attached, a saturated mono- or    bicyclic heterocycle having 3 to 10 ring members optionally    comprising another heteroatom chosen from oxygen, sulfur and    nitrogen and optionally being substituted by one or more alkyl,-   alk represents an alkyl or alkylene radical, the alkyl and alkylene    radicals and portions and the alkoxy radicals and portions have    straight or branched chains and comprise 1 to 6 carbon atoms and the    cycloalkyl radicals comprise 3 to 10 carbon atoms, the optical    isomers of these compounds and their pharmaceutically acceptable    salts with an inorganic or organic acid.

The preferred azetidine derivatives are as follows:

-   1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidine,-   b    1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetidine,-   1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl]-(methylsulfonyl)methylene}azetidine,-   1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)niethylene]azetidine,-   1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,-   (R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,-   (S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,-   1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoro-    methyl)phenyl]methylsulfonylmethylene}azetidine,-   (RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)ethylene]azetidine,-   (S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)ethylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmthyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,    1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(RS)-(4-chlorophenyl){4-[bis(2-methoxyethyl)aminomethyl]phenyl)methyl)}-3-[(3,5-difluorophenyl)(methylsulfonyl}methylene]azetidine,-   1-{{(R)-(4-chlorophenyl){4-[bis(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(S)-(4-chlorophenyl){4-[bis(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-[di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl}phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(morpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[(S)-(4-chlorophenyl)[4-(morpholin-4-ylmethyl)phenyl]methyl)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(piperazin-2-one-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(piperazin-2-one-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(piperazin-2-one-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-((4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)](methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine,-   1-(bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   (S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   (RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamoyl]phenyl}(methylsulfonyl)methylene}azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)phenyl](methylsulfonyl)-methylene}azetidine,-   1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(p-tolyl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   1-[(4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine,-   (RS)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(3-methoxycarbonylphenyl)(methylsulfonyl)methyl]azetidin-3-ol,-   1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(methylsulfonyl)(pyridin-4-yl)methyl]azetidin-3-ol,-   1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(methylsulfonyl)(pyridin-3-yl)methyl]azetidin-3-ol,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(3-(morpholin-4-yl)propyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(3-dimethylaminopropyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2-dimethylamino-1-methylethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(piperidin-1-yl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-isobutylbenzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(3-(imidazol-1-yl)propyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2-dimethylaminoethyl)benzamide,-   N′-methylhydrazide of    3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)benzoic    acid,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2-(morpholin-4-yl)ethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2,2-dimethylpropyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(cyclohexylmethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(cyclopropylmethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2-methylbutyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2-phenylpropyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2,2-diphenylethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-N-(2-ethylbutyl)benzamide,-   methyl ester of    4-{[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)-benzoylamino]methyl}cyclohexanecarboxylic    acid,-   2-amino-1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazin-1-yl}ethanone,-   tert-butyl ester of    (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic    acid,-   1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazin-1-yl}-2-(methylamino)ethanone,-   tert-butyl ester of    (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic    acid,-   N-methylamide of    4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazine-1-carbothioic    acid,-   N-methylamide of    4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazine-1-carboxylic    acid,-   methyl ester of    4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazine-1-carboxylic    acid,-   1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]-4-isobutylpiperazine,-   1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]-4-ethylpiperazine,-   4-acetyl-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazine,-   1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone,-   1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazine,-   tert-butyl ester of    4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(methanesulfonyl)methyl)phenyl]piperazine-1-carboxylic    acid,-   1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(RS)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine,-   (RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)(methanesulfonyl)methylene]azetidin-1-yl}methyl)benzyl]morpholine,-   4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)(methanesulfonyl)methyl]phenoxy}butyl)morpholine,-   4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)(methanesulfonyl)methyl]phenoxy}propyl)morpholine,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}thien-2-ylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methoxyphenylsulfonamide,-   N-[4-(N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}sulfamoyl)phenyl]acetamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methylphenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,4-dimethoxyphenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-fluorophenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,4-dichlorophenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-cyanophenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2,5-dimethoxyphenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-trifluoromethylphenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}naphth-2-ylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}naphth-1-ylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,4-difluorophenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-methyl-1H-imidazol-4-ylsulfonamide,-   N-[4-(N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}sulfamoyl)-2-chlorophenyl]acetamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}pyrid-3-ylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-fluorophenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}quinol-8-ylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}phenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(phenylmethyl)sulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,5-difluorophenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}pyrid-2-ylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-fluoro-5-pyrrolidin-1-ylphenyl)sulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl-4-fluorophenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methylquinol-8-ylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methylphenylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl(phenylmethyl)sulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-sulfamoylphenylsulfonamide,-   2-benzenesulfonyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}acetamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(4-toluene-4-sulfonyl)acetamide,-   (3-chloro-4-(methylsulfonyl)thiophene-2-carboxy)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]amide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-(2-phenylethylenesulfonyl)propionamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-(methylsulfonyl)benzamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-(methanesulfonyl)benzamide,-   (5-(methylsulfonyl)thiophene-2-carboxy)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}amide,-   (5-methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxy){1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}amide,-   (RS)-N-{1-[(4-chlorophenyl)(pyridin-3-yl)methyl]azetidin-3-yl}-3,5-difluorobenzenesulfonamide,-   (RS)-N-{1-[(4-chlorophenyl)(pyrimidin-5-yl)methyl]azetidin-3-yl}-3,5-difluorobenzenesulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6-chloropyrid-2-yl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6-ethylpyrid-2-yl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(quinol-6-yl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(quinol-5-yl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(isoquinol-5-yl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-3-yl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-1-oxide-3-yl)methylsulfonamide,-   N-(1R,2S,4S)-(bicyclo[2.2.1]hept-2-yl)-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide,-   N-(1R,2R,4S)-(bicyclo[2.2.1]hept-2-yl)-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(thiazol-2-yl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-methoxyphenyl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-hydroxyphenyl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-(hydroxymethyl)phenyl)methylsulfonamide,-   ethyl    N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(methylsulfonyl)-3-aminobenzoate,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(isobutylpiperid-4-yl)methylsulfonamide,-   N-benzyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}amine,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-3-ylmethyl)methylsulfonamide,-   N-{1-[bis(4-fluorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (RS)-N-{1-[(4-chlorophenyl)(pyrid-3-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (R)-N-{1-[(4-chlorophenyl)(pyrid-3-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (S)-N-{1-[(4-chlorophenyl)(pyrid-3-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (RS)-N-{1-[(4-chlorophenyl)(pyrid-4-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (R)-N-{1-[(4-chlorophenyl)(pyrid-4-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (S)-N-{1-[(4-chlorophenyl)(pyrid-4-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (RS)-N-{1-[(4-chlorophenyl)(pyrimidin-5-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (R)-N-{1-[(4-chlorophenyl)(pyrimidin-5-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   (S)-N-{1-[(4-chlorophenyl)(pyrimidin-5-yl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,-   N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)benzylsulfonamide,-   their optical isomers and their pharmaceutically acceptable salts    with an inorganic or organic acid.

And even more particularly preferred are the following azetidinederivatives:

-   1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol,-   3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(3,5-difluorophenyl)(methylulphonyl)methyl)methylsulfon    ylmethyl]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   their optical isomers and their pharmaceutically acceptable salts    with an inorganic or organic acid.

Mention may be made, as examples of pharmaceutically acceptable salts ofthe azetidine derivatives, of the following salts: benzenesulfonate,hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate,gluconate, iodate, isethionate, maleate, methanesulfonate,methylenebis-β-oxynaphthoate, nitrate, oxalate, pamoate, phosphate,salicylate, succinate, sulfate, tartrate, theophyllinacetate andp-toluenesulfonate.

Other CB1 receptor antagonists of use in the combinations according tothe invention are, for example, the pyrazole derivatives disclosed in EP576 357, EP 658 546, EP 656 354, WO 97/19063 and WO 00/46209, thebenzothiophene and benzofuran derivatives disclosed in WO 96/02248 orthe arylsulfonamides disclosed in WO 98/37061. Mention may in particularbe made of the products known under the code SR141716 and LY320135.

The synergistic effect of the combination of sibutramine and of a CB1receptor antagonist on food intake was determined according to thefollowing protocol:

Obese Fa/fa Zucker rats aged 7 weeks and originating from Iffa-Credo,France, were used in this study. The rats are housed in individual cagesand weighed every day between 8 and 10 o'clock in the morning. Theamount of food is also weighed each morning at the same time. This food(M20, Pietrement, France) is changed every day and the rats have freeaccess thereto for 24 hours. All the rats are treated for a week withthe vehicle (miglyol 812N and 0.5% methylcellulose/0.2% polysorbate 80)in two consecutive administrations. The rats are treated from the 8thday with the vehicle, the CB1 receptor antagonist(1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine)or sibutramine by the oral route (see table below).

The sibutramine is dissolved in a 0.5% methylcellulose/0.2% polysorbate80 solution and administered at a dose of 3 mg/kg; the CB1 receptorantagonist is dissolved in miglyol 812N (Hüls, Germany) at a dose of 0.6mg/kg and the two products are administered under a volume of 1 ml/kg.Each group is compose of 12 to 14 animals. The following groups areformed and the animals are treated for five days at the rate of twoconsecutive administrations every day. First Second GROUP administrationadministration 1 miglyol 0.5% methylcellulose/ “vehicle group” 0.2%polysorbate 2 miglyol sibutramine 3 mg/kg “sibutramine group” 3 CB1receptor 0.5% methylcellulose/ “CB1 receptor antagonist 0.2% polysorbateantagonist 0.6 mg/kg group” 4 CB1 receptor sibutramine 3 mg/kg“combination antagonist group” 0.6 mg/kg

The food consumption of each animal is measured every day. The resultsare expressed as mean amount of food consumed during the 5 days oftreatment. The results obtained are given in the table below. Foodconsumption during the Treatment 5 days of treatment (g) Vehicles 25.52± 0.30   sibutramine 3 mg/kg 24.60 ± 0.32*  CB1 receptor antagonist24.00 ± 0.24**  0.6 mg/kg sibutramine (3 mg/kg) + 22.76 ± 0.02*** CB1receptor antagonist (0.6 mg/kg)*p < 0.05**p < 0.01***p < 0.0001

The results show that, in the animals receiving the sibutramine and CB1receptor antagonist combination, the reduction in food consumption ismuch greater has that of the animals treated either with sibutraminealone or with the CB1 receptor antagonist alone.

The compounds of the combination can be employed orally, parenterally,transdermally or rectally, either simultaneously or separately or spreadout over time.

The present invention also relates to the pharmaceutical compositionscomprising the combination of sibutramine, its hydrate or one of itspharmaceutically acceptable salts and of a CB1 receptor antagonist inthe pure state or with one or more compatible and pharmacologicallyacceptable diluents and/or adjuvants and/or optionally in combinationwith another pharmaceutically compatible and physiologically activeproduct for a use which is either simultaneous or separate or spread outover time.

Use may be made, as solid compositions for oral administration, oftablets, pills, powders (hard gelatin capsules, cachets) or granules. Inthese compositions, the active principles are mixed with one or moreinert diluents, such as starch, cellulose, sucrose, lactose or silica,under an argon stream. These compositions can also comprise substancesother than the diluents, for example one or more lubricants such asmagnesium stearate or talc, a colorant, a coating (dragées) or a glaze.

Use may be made, as liquid compositions for oral administration, ofpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs comprising inert diluents, such as water, ethanol, glycerol,vegetable oils or liquid paraffin. These compositions can comprisesubstances other than the diluents, for example wetting, sweetening,thickening, flavouring or stabilizing products.

The sterile compositions for parenteral administration can preferably besolutions in aqueous or nonaqueous form, suspensions or emulsions. Usemay be made, as solvent or vehicle, of water, propylene glycol, apolyethylene glycol, vegetable oils, in particular olive oil, injectableorganic esters, for example ethyl oleate, or other suitable organicsolvents. These compositions can also comprise adjuvants, in particularwetting, isotonizing, emulsifying, dispersing and stabilizing agents.Sterilization can be carried out in several ways, for example by asepticfiltration, by incorporating sterilizing agents in the composition, byirradiation or by heating. They can also be prepared in the form ofsterile solid compositions which can be dissolved at the time of use insterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which comprise, in addition to the active product, excipientssuch as cocoa butter, semisynthetic glycerides or polyethylene glycols.

The pharmaceutical compositions generally comprise 0.5 to 10 mg ofsibutramine and 0.1 to 200 mg of the CB1 receptor antagonist.

The present invention also relates to the method for the treatment ofobesity which consists in administering, to the patient, a combinationaccording to the invention either simultaneously or separately or spreadout over time.

The doses depend on the desired effect, on the duration of treatment andon the administration route used; they are generally from 1 to 15 mg ofsibutramine per day by the oral route for an adult and from 0.10 to 500mg of the CB1 receptor antagonist per day by the oral route for anadult.

Generally, the doctor will determine the appropriate dosage according tothe age, weight and any other factor specific to the subject to betreated.

1. A combination of a CB1 receptor antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, wherein the CB1 receptor antagonist is: N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl) methylsulfonamide, or a pharmaceutically acceptable salt thereof.
 2. The combination according to claim 1, wherein the components of the combination are administered simultaneously, separately or spread out over time.
 3. The combination according to claim 1, wherein each component of the combination is administered in a single dose or in multiple doses.
 4. A composition comprising a CB1 receptor antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, wherein the CB1 receptor antagonist is: N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl) methylsulfonamide, or a pharmaceutically acceptable salt thereof.
 5. The composition according to claim 4, further comprising at least one compatible and pharmacologically acceptable diluent or adjuvant.
 6. The composition according to claim 4, comprising 0.5 to 10 mg of sibutramine and 0.1 to 200 mg of the CB1 receptor antagonist.
 7. The composition according to claim 4, further in combination with a pharmaceutically compatible and physiologically active product.
 8. The composition according to claim 5, further in combination with a pharmaceutically compatible and physiologically active product.
 9. A process for treating obesity in a mammal, comprising administering to the mammal in need thereof an effective amount of at least one CB1 receptor antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, wherein the CB1 receptor antagonist is: N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl) methylsulfonamide, or a pharmaceutically acceptable salt thereof.
 10. The process for treating obesity in a mammal according to claim 9, wherein sibutramine is administered at a concentration ranging from 0.5 to 10 mg and the CB1 receptor antagonist is administered at a concentration ranging from 0.1 to 200 mg.
 11. The process for treating obesity in a mammal according to claim 9, wherein the CB1 receptor antagonist and sibutramine are administered simultaneously, separately or spread out over time.
 12. The process for treating obesity in a mammal according to claim 9, wherein the CB1 receptor antagonist is administered in a single dose or in multiple doses.
 13. The process for treating obesity in a mammal according to claim 9, wherein sibutramine is administered in a single dose or in multiple doses. 